Positron emission tomography (PET) is a nuclear molecular imaging technique for real-time imaging of the human body using a radiation tracker labeled with an isotope which emits positrons. Positron emission tomography can effectively detect biochemical and physiological changes in vivo occurring in the early stage of diseases and thus is showing the most rapid growth in medical imaging markets. Among a variety of positron-emitting nuclides obtainable using a cyclotron or a generator, F-18 (half-life=110 min) is undergoing thorough research and applications.
Methods of labeling an organic compound with F-18 may largely include an electrophilic substitution reaction and a nucleophilic substitution reaction. Particularly useful is a nucleophilic substitution reaction using [18F]fluoride anions having high specific activity. Compared to other nucleophiles, an [18F]fluoride nucleophile has lower reactivity, and may be subjected to a labeling reaction at a relatively high temperature and needs a comparatively large amount of precursor compound. The precursor means a compound having a leaving group which enables [18F]fluoride to perform nucleophilic attack, that is, a compound having a leaving group instead of F-18 in an F-18 labeled compound. [18F]Fluoride produced by a cyclotron is provided in the form of a metal salt in a state of being dissolved in an [18O]H2O aqueous solution, and a cartridge having an anion exchange resin is used to refine [18F]fluoride and to remove an excess of water. When the [18F]fluoride aqueous solution is allowed to flow to the cartridge, only the [18F]fluoride is captured, and the other metal salt and water are removed. The [18F]fluoride solution is eluted from the [18F]fluoride-captured cartridge using an appropriate electrolyte solution. The eluted [18F]fluoride solution contains a large amount of water, and a dewatering process is thus required, which is typically performed for 15˜20 min. Because the half-life of F-18 is 110 min, the dewatering process results in a decrease in radiation dose of about 10%.
In order to increase reactivity of the [18F]fluoride, various phase transfer catalysts have been used. Currently, kryptofix[2.2.2] is very useful. Although kryptofix is commercially available, it is very expensive and has high toxicity. Also, because the half-life of F-18 is short, a labeling reaction should be rapidly carried out to produce [18F]radiopharmaceuticals in high yield. An excess of precursor is typically used to achieve a rapid labeling reaction, but the excess of precursor used is left as an impurity along with byproducts after the labeling reaction. Consequently, the purification process of [18F]radiopharmaceuticals may become complicated or the purity of refined [18F]radiopharmaceuticals may be lowered.
With the goal of effectively removing the reaction byproducts and unreacted precursor, some methods have been developed in which the structure of the sulfonate leaving group of the precursor is modified.
Specifically, it was reported that an insoluble polymer having a sulfonyl chloride functional group is used to synthesize a perfluoroalkyl sulfonate precursor supported to the polymer, which is then easily removed via filtration after the reaction (WO 2005/012319 A1; L, J. Brown, Angew. Chem. Int. Ed., 46, 941-944, 2007). However, the preparation of the insoluble polymer having the perfluoroalkane sulfonyl chloride functional group is considerably complicated, and there is little analytical data for the polymer at individual steps, making it difficult to reproduce the above procedures. Further, most of the compounds after the reaction may be released from the polymer into a reaction solution due to the side reactions, and thus there is no effect for compound purification unlike original purposes.
Examples of the polymer developed to perform an F-18 labeling reaction to date include 1) an anion exchange resin for use in refining [18F]fluoride from a metal salt aqueous solution, and 2) a polymer type precursor. In respective cases, polymer structures and purposes of use thereof are independent of each other.
The present inventors have paid attention to precursors having an organic salt which induces an intramolecular nucleophilic substitution reaction, and therefore have developed a solid precursor having an organic salt connected to a solid support and confirmed that such a precursor may refine [18F]fluoride in an [18F]fluoride aqueous solution, and also the organic salt acts as an intramolecular phase transfer catalyst so that on-resin or on-cartridge [18F]fluorination may be carried out, thus culminating in the present invention.